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Glycoconjugates of RNA interference agents

a technology of rna interference and glycoconjugates, which is applied in the direction of sugar derivatives, biochemistry apparatus and processes, organic chemistry, etc., can solve the problems of insufficient safety and/or efficiency of nucleic acid delivery systems, the inability of nucleic acid molecule to disrupt the natural functions of cells as little as possible, and the inability to meet the needs of cell function, etc., to inhibit the expression of a target gene, the effect of inhibiting th

Active Publication Date: 2014-11-04
ALNYLAM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides an RNAi agent that can inhibit the expression of a target gene in a cell. The RNAi agent is made up of two mutually complementary oligoribonucleotide strands, which are attached to a ligand containing a linker group and a galactose moiety. The distance between the galactose moieties can range from at least 4 to 20 Å. The RNAi agent is effective in inhibiting the expression of the target gene and may be used in treating diseases or conditions related to unwanted expression of a target gene in the liver. The cell harboring asialoglycoprotein receptor on its surface can be a hepatocyte. The invention also provides a pharmaceutical composition containing the RNAi agent and a method for introducing it into a cell and treating a subject with the pharmaceutical composition. The cell carrying the RNAi agent is a hepatocyte.

Problems solved by technology

If RNA interference is to live up to its potential, the process of introducing the nucleic acid molecule should disrupt the natural functions of the cell as little as possible, particularly where the cell is part of a living organism.
Numerous solutions have been proposed, none of which is so far fully satisfactory.
The available nucleic acid delivery systems are not yet satisfactory in terms of safety and / or efficiency for their utilization in in vitro experimental applications and / or human diagnosis and therapy, and require further optimization.

Method used

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  • Glycoconjugates of RNA interference agents
  • Glycoconjugates of RNA interference agents
  • Glycoconjugates of RNA interference agents

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1. Materials

[0266]Where the source of a reagent is not specifically given herein, such reagent may be obtained from any supplier of reagents for molecular biology at a quality / purity standard for application in molecular biology.

Synthesis of 1-O-{4-[(2-cyanoethoxy)-N,N-diisopropylamino-phosphanyloxy]-butyl}-6-O-(4-methoxytriphenylmethyl)-2,3,4-tri—O-acetyl-B-D-galactopyranoside (9)

[0267]The synthesis of compound 9 is illustrated in FIG. 6. 20 g (51.24 mmol) of β-D-galactosepentaacetate 1 was dissolved in 150 ml THF and 6.7 ml (61.49 mmol) of benzylamine was added with a dropping funnel. The reaction was stirred for 18 h at room temperature to give 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 2.

[0268]Product 2 was dissolved in 50 ml (240 mmol) trichloacetonitrile and cooled down to −20° C. Within 15 min 3.56 ml (23.96 mmol) of 1,8-Diazabicyclo[5.4.0]-undec-7-ene were added using a dropping funnel. After 1.5 h synthesis of 2,3,4,6-tetra-O-acetyl-D-galactopyranosyl-trichloroacetimidate 3...

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Abstract

The present invention relates to agents, compositions and methods for inhibiting the expression of a target gene, comprising an RNAi agent bearing at least one galactosyl moiety. These are useful for delivering the gene expression inhibiting activity to cells, particularly hepatocytes, and more particularly in therapeutic applications.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 925,880, filed Apr. 23, 2007; the entirety of which is hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates to agents, compositions and methods for inhibiting the expression of a target gene, comprising an RNAi agent bearing at least one galactosyl-moiety. These are useful for delivering the gene expression inhibiting activity to cells, particularly hepatocytes, and more particularly in therapeutic applications.BACKGROUND OF THE INVENTION[0003]RNA interference (RNAi) is an evolutionarily conserved, sequence specific mechanism triggered by double stranded RNA (dsRNA) that induces degradation of complementary target single stranded mRNA and “silencing” of the corresponding translated sequences (McManus and Sharp, Nature Rev. Genet. 2002, 3:737; Mello and Donte, Nature 2004, 431:338; Meister and Tuschl, Nature 2004, 431:343; ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C12N15/113C07H21/04A61K47/48C12N15/11
CPCC12N2320/32C12N15/113A61K47/48092C12N15/111A61K47/48215C12N2310/351C12N2310/14C12N2310/315C12N2310/321A61K31/713
Inventor FORST, ANDREAHADWIGER, PHILIPPVORNLOCHER, HANS-PETER
Owner ALNYLAM PHARMA INC
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